Even though significant advances have occurred in treatment of cancer, it still remains a major health concern. It has been reported that cancer is the cause of death of up to one of every four Americans.
Included among the known chemotherapeutic drugs are carmustine, doxorubicin, methotrexate, TAXOL, nitrogen mustard, procarbazine, and vinblastine, to name only a few. However, many chemotherapeutic drugs also produce undesirable side effects in the patient. For example, U.S. Pat. No. 4,717,726 reportedly discloses a compound suitable for inhibiting the growth of certain types of malignant neoplasms in mammals. See also Plowman et al., Cancer Res., 49 (1989), 1909–1915. The disclosed compound, 3,5-dichloro-2,4-dimethoxy-6-(trichloromethyl) pyridine, also known as penclomedine, is not satisfactory as a chemotherapeutic, however, because it is known to produce certain undesirable side effects especially in the central nervous system.
Penclomedine (PEN) was evaluated in Phase I clinical trials at Johns Hopkins University Oncology Center, the University of Wisconsin Comprehensive Cancer Center and Western General Hospital in Edinburgh. Hartman et al. Murine and human in vivo penclomedine metabolism; Clin Cancer Res 2: 953, 1996; O'Reilly et al., Tissue and tumor distribution of 14C-penclomedine in rats; Clin Cancer Res 2:541; 1996; Berlin et al., Phase I clinical and pharmacokinetic trial of penclomedine using a novel, two-stage trial design for patients with advanced malignancy; J Clin Oncol 16:1142; 1998; O'Reilly et al., Phase I and pharmacologic studies of penclomedine, a novel alkylating agent in patients with solid tumors; J Clin Oncol 15:1974; 1997 and Jodrell et al., Dose-limiting neurotoxicity in a phase I study of penclomedine (NSC 388720, CRC 88-04), a synthetic alpha-picoline derivative, administered intravenously; Brit J Cancer 77: 808; 1998) for possible use in the treatment of breast cancer, based on activity against human breast tumor xenografts and experimental mammary tumor models. Plowman et al., Preclinical antitumor activity of an alpha-picoline derivative, penclomedine (NSC 338720), on human and murine tumors; Cancer Res 49: 1909; 1989; and Harrison et al., Preclinical antitumor activity of penclomedine in mice; cross-resistance, schedule-dependence, and oral activity against tumor xenografts in brain; Cancer Res 51: 1979; 1991) and in the treatment of brain tumors, based on its activity against tumor xenografts in the brain (see Harrison et al; supra).
In all of these clinical trials, dose-limiting neurotoxicity was observed after both intravenous and oral administration and was related to peak plasma levels of PEN (see O'Reilly et al; J. Clin Oncol. 12:1974, supra).
The presence of these toxicities, at much lower peak plasma concentrations compared to those reported in preclinical studies, may preclude the administration of higher doses of penclomedine and the achievement of concentrations associated with optimal antitumor activity. Berlin et al., Proc. Amer. Assoc. Cancer Res., 36, 238 (1005); O'Reilly et al., Proc. Amer. Soc. Clin. Oncol., 14, 471 (1995).
Some relevant background art can be found in O'Reilly et al., Clinical Cancer Research, 2 (March 1996), 541–548. This reference describes a study to assess the distribution of 14C-penclomedine in the tissues and tumors of tumor-bearing rats. The study found that the predominant radioactive species in the brain was penclomedine, which may explain the observed neurotoxicity of the drug.
4-Demethylpenclomedine (DM-PEN) was identified as the major plasma metabolite in patients and rodents (see Hartman et al., Clin Cancer Res. 2:953, supra and O'Reilly et al; Clin Cancer Res. 2:541; supra), and neuroanatomic studies of PEN and DM-PEN in rats revealed cerebellar damage only in the PEN-treated group (see O'Reilly et al, The alkylating agent penclomedine induces degeneration of purkinje cells in the rat cerebellum; Invest New Drugs 21:269; 2003).
3,5-Dichloro-2-methoxy-4-hydroxy-6-(trichloromethyl)pyridine or 4-demethylpenclomdine has been suggested as a compound for treating cancer. See WO 97/46531 to Hartman et al. Also see Waud et al., 4-Demethylpenclomedine, an antitumor-active, potentially normeurotoxic metabolite of penclomedine; Cancer Res, 57:815; 1997.
More recently, a series of acyl derivatives of DM-PEN was prepared and evaluated against MX-1 tumor xenografts, several other human tumor xenografts and murine P388 leukemia, revealing potent activity (see Struck et al; Acyl derivatives of demethylpenclomedine, an antitumor active, normeurotoxic metabolite of penclomedine, Cancer Chemotherap Pharmacol 48:47; 2001; U.S. Pat. No. 6,376,518 to Struck and U.S. Pat. No. 6,391,893 to Struck et al.).
Notwithstanding the advances in cancer treatment that have been made, there still remains room for improved drugs that are effective in treating cancer, while at the same time exhibit reduced adverse side effects.